Olfaction is mediated in mammals by the main olfactory system and the accessory olfactory (or vomeronasal) systems. The traditional view is that the former mediates the detection of 'common' odorants, while the latter is primarily responsible for the recognition of pheromones. The molecular and physiologal approaches to the vomeronasal system have been insufficiently integrated. In recent work, the Celera mouse database was mined to characterize sequence diversity of the mouse VIR repertoire. A strain of mice was developed in which a cluster of 16 VIR genes, encompassing 2/12 VIR families, has been deleted by chromosome engineering. Both male and female mutant mice show specific behavioral deficits, providing the first link between VIR genes and pheromone-associated behaviors. Five intact VIR-like receptor genes have been identified in the human genome. A novel assay has been developed to measure physiological responses of vomeronasal sensory neurons. Here, a combined approach is proposed to test the hypothesis that vomeronasal receptors are responsible for the detection of pheromones and other socially important molecules. Aim 1: To characterize the phenotype of mutant mouse strains that lack various clusters of vomeronasal receptor genes as a result of chromosome engineering. Aim 2: To express human vomeronasal receptors functionally in neurons of mice. Aim 3: To characterize the mouse V2R repertoire by bioinformatics, followed by targeted deletions qf selected V2R gene clusters. Aim 4: To develop mouse strains in which one of the two populations of vomeronasal sensory neurons is marked, and test physiologically if they correspond to dual chemosensory modalities. Two laboratories with proven and complementary expertise in the vomeronasal system propose to join forces to solve these difficult and outstanding biological issues. The results will provide new insights into the biology of pheromone communication in mammals.